Hepatocellular carcinoma in a young dog

Abstract

A 25-month-old Chihuahua dog with no clinical signs was evaluated for high serum liver enzymes. Ultrasonography and computed tomography revealed a mass in the left hepatic medial lobe. The histological diagnosis reached using resected tissues was hepatocellular carcinoma (HCC). To the authors’ knowledge, this is the youngest dog diagnosed with HCC.

Case description

A 25-month-old 2.2-kg castrated male Chihuahua dog was referred to the Veterinary Medical Teaching Hospital at the Nippon Veterinary and Life Science University for further evaluation of abnormal serum liver enzyme activity. The dog had no clinical signs and had been presented to the referring veterinarian for a routine medical examination. Blood screening revealed high serum liver enzymes: aspartate transaminase [AST, 53 U/L; reference range (RR): 14 to 44 U/L], alanine aminotransferase (ALT, 169 U/L; RR: 14 to 68 U/L), alkaline phosphatase (ALP, 1934 U/L; RR: 47 to 254 U/L), and gamma-glutamyl transpeptidase (GGT, 424 U/L; RR: 2 to 15 U/L). The referring veterinarian initiated treatment with ursodeoxycholic acid at a dose of 11 mg/kg body weight (BW), PO, q24h for 1 mo prior to referral.

At the time of initial evaluation at our veterinary medical teaching hospital, the dog’s general condition was normal on physical examination. A complete blood (cell) count (CBC), coagulation profile, and blood gas analysis were also normal. Results of a serum biochemical analysis revealed high serum activities of AST (55 U/L), ALT (124 U/L), ALP (2321 U/L), and GGT (420 U/L). Additionally, the serum alpha-fetoprotein (AFP) concentration was 336 ng/mL (RR: 2.5 to 50.0 ng/mL) measured by latex agglutination immunoassay (Lamute Canine AFP N; Shima Laboratories, Tokyo, Japan).

Thoracic and abdominal radiographs were unremarkable. However, abdominal ultrasonography revealed a nodular mass (2.6 × 2.5 cm) in the left portion of the liver (Figure 1). The mass was mildly hyperechoic and heterogeneous, and the other liver lobes appeared normal. Neither enlarged intra-abdominal lymph nodes nor peritoneal effusion was seen.

Figure 1.

Transverse ultrasonographic view of the liver showing the mildly hyperechoic and heterogeneous mass (arrows) in the left portion of the liver.

A computed tomography (CT) study of the abdomen and thorax was performed to define the extent of the mass and determine whether there was metastasis. Dynamic CT scanning of the liver was initiated at the cranial aspect of the diaphragm and extended caudally to the level of the pelvic inlet. In the arterial phase, the scanning extended caudally to the liver margin. Iopamidol (Schering, Osaka, Japan), 1.2 g/kg BW was injected with a power injector over 8 s via the jugular vein. Images were obtained before contrast medium injection, in the arterial phase just after contrast medium injection, and in the portal venous (13 s) and equilibrium (75 s) phases after contrast injection. The mass was isoattenuating during precontrast scanning (Figure 2A) and hyperattenuating during the arterial phase (Figure 2B). In contrast, the surrounding liver was hypoattenuating during the portal venous and equilibrium phases (Figures 2C, 2D). Lesions in other liver lobes and metastases were not observed.

Figure 2.

Computed tomographic images before and after administration of contrast medium. A — Precontrast image. B — Arterial phase. C — Portal venous phase. D — Equilibrium phase. The mass in the left medial liver lobe is hyperattenuating in the arterial phase and washed out in the portal venous and equilibrium phases.

On day 10, partial left medial hepatic lobectomy was performed to excise the mass (Figure 3). Grossly, the mass measured 3.3 × 3.3 × 2.0 cm and was located in the left medial lobe. The cut surface of the mass was gray-white. Histologically, the mass was composed of a proliferation of hepatocellular neoplastic cells arranged in a solid pattern (Figure 4A). The tumor did not have normal architectural arrangement of portal triads. Neoplastic cells had round nuclei and relatively broad, eosinophilic cytoplasm, which was often vacuolated (Figure 4B). The frequency of mitotic figures was 0–1 per high-power field (400× magnification). The final diagnosis was hepatocellular carcinoma (HCC).

Figure 3.

Appearance of a mass in the left medial lobe (arrows) of the liver (head is up).

Figure 4.

Microscopic appearance of a left medial liver lobe mass. A — The mass is composed of the proliferation of hepatocellular neoplastic cells. The border between the cells is distinct (arrows). H&E stain; bar = 100 μm. B — Neoplastic cells have eosinophilic cytoplasm that is often vacuolated, a mitotic figure (arrow) is shown. H&E stain; bar = 25 μm.

The dog recovered well after surgery and was discharged on postoperative day 8. Serum liver enzyme levels at discharge were still increased: ALT: 192 U/L, ALP: 1507 U/L, and GGT: 199 U/L, but AST was within normal limits at 33 U/L. The serum AFP concentration of 85 ng/mL was decreased but still high. At postoperative day 33, the serum liver enzymes were improved: AST: 39 U/L, ALT: 65 U/L, ALP: 207 U/L, and GGT: 12 U/L. Furthermore, the serum AFP concentration was normal at 30 ng/mL. More than 200 days after the surgery, the general condition of the dog was stable and the serum liver enzymes and serum AFP remained within normal reference ranges.

Discussion

Primary liver tumors are uncommonly reported in dogs and account for only 0.6% to 1.3% of all canine neoplasms (1). The most common primary liver tumor is HCC, although other malignant tumors can occur, including bile duct carcinoma, carcinoids, and sarcomas (2,3). The average age of onset is 11 years, and 80% are older than 10 years, with males predominating (1,2). The gross morphology of HCC is described as massive, nodular, or diffuse. In previous reports, massive HCC, defined as a large tumor affecting a single liver lobe, represented 61% of all canine HCCs and nearly 70% reportedly occurred on the left side (1,4,5). In contrast, nodular HCC involving more than 1 liver lobe, and diffuse HCC accounted for 29% and 10%, respectively (1). The metastatic rate varied from 4.8% to 61%, and metastasis is more common for nodular and diffuse forms than for the massive form (1,5). Factors indicating a poor prognosis include high serum ALT and AST levels, because these may be caused by aggressive biological tumor behavior, such as fast growth rate or large size (5). In previous reports, more than 1 liver enzyme was high in almost all dogs with HCC, and ALP and ALT were most often increased (1,4,5). Most frequently, all 4 liver enzymes were increased (5). Our case had an increase of all liver enzymes, but the increase in serum ALT and AST was mild. Compared with 1 previous report (5), the serum GGT elevation was marked. In dogs, moderate to marked increases in GGT are seen with intrahepatic and extrahepatic cholestasis, but in this case there was no other indication of cholestasis, such as high serum total bilirubin, biliary sludge, or dilation of the bile ducts.

A high intraoperative mortality rate has been associated with right-sided tumors, but there is no significant difference in survival time between left-sided and right-sided tumors when intraoperative deaths are taken out of the analysis (5). The reason the dog in this case developed HCC at such a young age is unknown. However, it was fortunate that the HCC was a raised solitary mass in the left medial lobe with no metastasis.

Serum AFP concentration is used in both humans and dogs to diagnose HCC (6–8). In a previous report of 4 dogs with HCC, 3 dogs that had well-differentiated HCC had elevated AFP levels, while the single dog with a poorly differentiated HCC had a normal AFP level (8). The serum AFP concentration in all dogs with HCC decreased rapidly after removal of the tumor (7,8). Dogs with low AFP concentrations had no recurrence of the tumor; however, recurrence was seen in cases in which the AFP concentrations gradually increased (7,8). In the present case, similar to previous reports, the preoperative serum AFP concentration was high but returned to normal after removal of the mass.

In humans, HCC is frequently associated with chronic liver diseases, such as cirrhosis and infection with hepatitis viruses. Currently, the diagnosis of HCC is highly dependent on radiological hallmarks, such as arterial hypervascularity and venous/ late phase washout, and several guidelines exist. According to the guidelines of the European Association for Study of the Liver-European Organization for Research and Treatment of Cancer (EASL-EORTC) (9), although non-invasive criteria can only be applied to cirrhotic patients, a diagnosis of HCC is established by either 1 imaging technique showing nodules above 2 cm and a HCC radiological hallmark, or 2 coincidental imaging techniques with nodules of 1–2 cm in diameter. Alpha-fetoprotein levels were dropped from the guidelines (9). The recent updated guidelines of The American Association for Study of Liver Diseases (AASLD) proposed that 1 imaging technique such as CT or MRI showing a HCC radiological hallmark suffices for diagnosing tumors of 1–2 cm in diameter (10). Hepatocellular carcinoma is a hypervascular tumor with increased blood supply. Classically the tumor demonstrates hepatic arterial enhancement. Two important diagnostic features have emerged from the EASL and AASLD consensus criteria: i) hypervascularity in the hepatic arterial phase, and ii) wash-out in the portal venous phase. In veterinary medicine, it has been reported that dogs with HCC have low attenuation in the portal venous and equilibrium phases (11). Additionally, canine HCCs tend to have central or marginal enhancement, whereas hepatic adenoma is more likely to have diffuse enhancement in the arterial phase (11). Hypoattenuation in the later phases is also characteristic for HCC, whereas contrast retention in the portal venous and equilibrium phases is characteristic for benign hepatic lesions such as hepatic adenoma and nodular hyperplasia (11). In this case, the mass had overall enhancement in the arterial phase, but hypoattenuation in the portal venous and equilibrium phases. The findings in this case were consistent with the characteristics of HCC.

Young dogs with HCC are rare, and to the authors’ knowledge, this is the youngest dog reported with HCC. Computed tomographic findings and serum AFP concentrations are useful in diagnosing canine HCC, and should be included in a list of tests for hepatic masses, even in young canines. CVJ